A Study of Subcutaneous Abatacept to Treat Diffuse Cutaneous Systemic Sclerosis

Diffuse Cutaneous Systemic Sclerosis Clinical Trial

— ASSET  

Official title:

A Phase 2 Study to Evaluate Subcutaneous Abatacept vs. Placebo in Diffuse Cutaneous Systemic Sclerosis- a Double-blind, Placebo-controlled, Randomized Controlled Trial.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02161406
• Other study ID #: IM101-344
• Secondary ID: 1UM1AI110557
• Status: Completed
• Phase: Phase 2
• Start date: September 2014
• Est. completion date: October 17, 2018

Study information

• Verified date: February 2020
• Source: University of Michigan
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The study hypothesis is that SC abatacept is safe and shows evidence of efficacy (improvement in modified Rodnan score [mRSS]) in patients with diffuse cutaneous systemic sclerosis (dcScc) compared to matching placebo.

Description:

This study is a randomized placebo-controlled double-blind phase 2 trial of patients with dcSSc. Eligible participants will be randomized in a 1:1 ratio to either 125 mg SC abatacept or matching placebo, stratified by duration of dcSSc disease duration (<18 months vs >18 to

Recruitment information / eligibility

• Status: Completed
• Enrollment: 88
• Est. completion date: October 17, 2018
• Est. primary completion date: September 12, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Diagnosis of Systematic Sclerosis (SSc), as defined using the 2013 American College of Rheumatology/ European Union League Against Rheumatism classification of SSc

2. Diffuse Systemic Sclerosis (dcSSc) as defined by LeRoy and Medsger

3. Disease duration of = 36 months (defined as time from the first non-Raynaud phenomenon manifestation)

4. For disease duration of = 18 months: = 10 and = 35 mRSS units at the screening visit

5. For disease duration of >18-36 months: = 15 and = 45 mRSS units at the screening visit and one of the following:

• Increase = 3 in mRSS units compared with the last visit within previous 1-6 months

• Involvement of one new body area with = 2 mRSS units compared with the last visit within the previous 1-6 months

• Involvement of two new body areas with = 1 mRSS units compared with the last visit within the previous 1-6 months

• Presence of 1 or more Tendon Friction Rub

6. Age = 18 years at the screening visit

7. If female of childbearing potential, the patient must have a negative pregnancy test at screening and baseline visits

8. Oral corticosteroids (= 10 mg/day of prednisone or equivalent) and NSAIDs are permitted if the patient is on a stable dose regimen for

• 2 weeks prior to and including the baseline visit.

9. ACE inhibitors, calcium-channel blockers, proton-pump inhibitors, and/or oral vasodilators are permitted if the patient is on a stable dose for = 2 weeks prior to and including the baseline visit.

Exclusion Criteria:

1. Rheumatic disease other than dcSSc; it is acceptable to include patients with fibromyalgia and scleroderma-associated myopathy

2. Limited cutaneous systemic sclerosis or sine scleroderma at the screening visit

3. Major surgery (including joint surgery) within 8 weeks prior to screening visit

4. Infected ulcer prior to randomization

5. Treatment with any investigational agent within = 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of the baseline visit

6. Previous treatment with cell-depleting therapies, including investigational agents, including but not limited to, CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, and ABA

7. Anti-CD20, and cyclophosphamide within 12 months prior to baseline visit.

8. Use of Intravenous Immunoglobulin (IVIG) within 12 weeks prior to baseline visit

9. Previous treatment with chlorambucil, bone marrow transplantation, or total lymphoid irradiation

10. Immunization with a live/attenuated vaccine within = 4 weeks prior to the baseline visit

11. Treatment with methotrexate, hydroxychloroquine, cyclosporine A, azathioprine, mycophenolate mofetil rapamycin, colchicine, or D-penicillamine, within= 4 weeks prior to the baseline visit

12. Treatment with etanercept within = 2 weeks, infliximab, certolizumab, golimumab, ABA or adalimumab within = 8 weeks, anakinra within = 1 week prior to the baseline visit

13. Pulmonary disease with FVC = 50% of predicted, or DLCO (uncorrected for hemoglobin ) = 40% of predicted at the screening visit

14. Pulmonary arterial hypertension (PAH) as determined by right heart catheterization or on PAH approved medications for PAH. It is acceptable to use PDFE-5 inhibitors for Raynaud's and digital ulcers.

15. Subjects at risk for tuberculosis (TB). Specifically excluded from this study will be participants with a history of active TB within the last 3 years, even if it was treated; a history of active TB greater than 3 years ago, unless there is documentation that the prior anti-TB treatment was appropriate in duration and type; current clinical, radiographic, or laboratory evidence of active TB; and latent TB that was not successfully treated (= 4 weeks).

16. Positive for hepatitis B surface antigen prior to the baseline visit

17. Positive for hepatitis C antigen, if the presence of hepatitis C virus was also shown with polymerase chain reaction or recombinant immunoblot assay prior to baseline visit

18. Subjects at risk for tuberculosis (TB). Specifically excluded from this study will be participants with a history of active TB within the last 3 years, even if it was treated; a history of active TB greater than 3 years ago, unless there is documentation that the prior anti-TB treatment was appropriate in duration and type; current clinical, radiographic, or laboratory evidence of active TB; and latent TB that was not successfully treated (= 4 weeks).

19. Any of the following at the screening visit: Hemoglobin <8.5 g/dL; WBC < 3,000/mm3 (<3 x 109/L); platelets < 100,000/mm3 (<3 x 109/L); serum creatinine > 2 x ULN; serum ALT or AST > 2 x ULN

20. Severe skin thickening (mRSS 3) on the inner aspects of thighs, upper arms, or abdomen

21. Patients with a history of anaphylaxis to abatacept

Related Conditions & MeSH terms

• Diffuse Cutaneous Systemic Sclerosis
• Scleroderma, Diffuse
• Scleroderma, Systemic
• Sclerosis

Intervention

Drug:
• Abatacept
Subjects will be treated with injections of 125 mg of abatacept or placebo weekly for 52 weeks
• Placebo
125 mg of Placebo

Locations

Country	Name	City	State
Canada	St. Joseph Health Care London	London	Ontario
Canada	Jewish General Hospital	Montreal	Quebec
Canada	Mount Sinai Hospital	Toronto	Ontario
United Kingdom	Royal Free Hospital	London
United States	Steffens Scleroderma Center	Albany	New York
United States	University of Michigan	Ann Arbor	Michigan
United States	Boston University	Boston	Massachusetts
United States	Harvard Mass General	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Northwestern University	Chicago	Illinois
United States	Cleveland Clinic	Cleveland	Ohio
United States	Ohio State University Medical Center	Columbus	Ohio
United States	NorthWell Health	Great Neck	New York
United States	University of Texas Health Center at Houston	Houston	Texas
United States	Arthritis Associates of Southern California	Los Angeles	California
United States	University of California- Los Angeles	Los Angeles	California
United States	University of Minnesota	Minneapolis	Minnesota
United States	Rutgers University Clinical Research Center	New Brunswick	New Jersey
United States	Columbia University	New York	New York
United States	Hospital for Special Surgery	New York	New York
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Stanford University	Redwood City	California
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Utah	Salt Lake City	Utah
United States	Swedish Health Services	Seattle	Washington
United States	Georgetown University	Washington	District of Columbia

Sponsors (3)

Lead Sponsor	Collaborator
Dinesh Khanna, MD, MS	Bristol-Myers Squibb, National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Canada,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of Participants With at Least One Adverse Events (AEs) or Serious AEs (SAEs) in 1 Year	Safety is measured using AEs, including clinical significant changes in vital signs, laboratory test abnormalities and clinical tolerability of abatacept, and using serious AEs	52 weeks
Primary	Change From Baseline in the Modified Rodnan Skin Score (mRSS) to Month 12	The efficacy of treatment on skin fibrosis will be measured by changes from baseline to month 12 in mRSS, a measure of skin thickness. mRSS scores have a range from 0 to 51, with higher score indicating greater severity of SSc (worse outcome).	Baseline and 52 weeks
Secondary	Change From Baseline to Month 12 in Patient Global Assessment for Overall Disease	Patient global assessment for overall disease represents the patient's assessment of the patient's global scleroderma on a 0 (excellent) -10 (extremely poor) Likert scale. Higher score means worse outcome.	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in Physician Global Assessment for Overall Disease	This assessment represents the physician's assessment of the patient's current disease activity on a 0 (excellent) -10 (extremely poor) Likert scale. Higher score means worse outcome.	Baseline and Week 52
Secondary	Change in % Predicted FVC	FVC is Forced vital capacity, a measure of lung function. FVC % Predicted is calculated using equations from Hankinson [Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med. 1999;159(1):179-87], incorporating age, gender, and race. It is calculated as the (FVC Observed / FVC predicted) * 100, where FVC predicted is calculated relative to a reference population.	Baseline and 52 weeks
Secondary	Change From Baseline to Month 12 in FVC (in ml)	FVC = forced vital capacity, a measure of lung function	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in HAQ-DI - Overall	The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI overall score ranges from 0 (no disability) to 3 (severe disability). Higher score means worse outcome.	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in SHAQ-DI VAS - Overall Disease	Scleroderma-Health Assessment Question Disability Index visual analogue scales (VAS) assess the burden of digital ulcers, Raynaud's, gastrointestinal involvement, breathing, and overall disease. The VAS scale for disease severity ranges from 0 (no disease) to 150 (very severe). A higher score means a worse outcome.	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in SHAQ-DI VAS - Breathing	Scleroderma-Health Assessment Question Disability Index visual analogue scales (VAS) assess the burden of digital ulcers, Raynaud's, gastrointestinal involvement, breathing, and overall disease. The VAS scale for how much breathing problems interfered with daily activities ranges from 0 (do not limit activities) to 150 (very severe limitation). A higher score means a worse outcome.	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in SHAQ-DI VAS - Raynaud's	Scleroderma-Health Assessment Question Disability Index visual analogue scales (VAS) assess the burden of digital ulcers, Raynaud's, gastrointestinal involvement, breathing, and overall disease. The VAS scale for how much Raynaud's interfered with daily activities ranges from 0 (does not limit activities) to 150 (very severe limitation). A higher score means a worse outcome.	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in SHAQ-DI VAS - Burden of Digital Ulcers	Scleroderma-Health Assessment Question Disability Index visual analogue scales (VAS) assess the burden of digital ulcers, Raynaud's, gastrointestinal involvement, breathing, and overall disease. The VAS scale for how much finger ulcers interfered with daily activities ranges from 0 (do not limit activities) to 150 (very severe limitation). A higher score means a worse outcome.	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in SHAQ-DI VAS - GI Involvement	Scleroderma-Health Assessment Question Disability Index visual analogue scales (VAS) assess the burden of digital ulcers, Raynaud's, gastrointestinal involvement, breathing, and overall disease. The VAS scale for how much intestinal problems interfered with daily activities ranges from 0 (do not limit activities) to 150 (very severe limitation). A higher score means a worse outcome.	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in Swollen Joint Count	28 joints are assessed for swelling (positive or negative). The number of swollen joint count ranges from 0 to 28. A higher number indicates worse outcome.	Baseline and 52 weeks
Secondary	Change From Baseline to Month 12 in Tender Joint Counts	28 joints are assessed for tenderness (positive or negative). The number of tender joint counts ranges from 0 to 28. A higher number indicates worse outcome.	Baseline and 52 weeks
Secondary	Change From Baseline to Month 12 in PROMIS-29 - Physical Function	The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the physical function domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., better outcome).	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in PROMIS-29 - Anxiety	The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the anxiety domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., worse outcome).	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in PROMIS-29 - Depression	The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the depression domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., worse outcome).	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in PROMIS 29 - Fatigue	The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the fatigue domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., worse outcome).	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in PROMIS-29 - Sleep Disturbance	The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the sleep disturbance domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e.,worse outcome).	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in PROMIS-29 - Pain Interference	The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the pain interference domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., worse outcome).	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in PROMIS-29 - Ability to Participate in Social Roles & Activities	The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the ability to participate in social roles and activities domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., better outcome).	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in PROMIS-29 - Pain Intensity	The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the pain intensity domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., worse outcome).	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in SCTC GIT - Composite Score	The SCTC GIT is the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Instrument. It assesses scleroderma-related gastrointestinal symptoms. The composite score ranges from 0 to 2.83; 0 indicates better health and higher score indicates worse health.	Baseline and Week 52
Secondary	ACR CRISS at 12 Months	The American College of Rheumatology Combined Response Index in Systemic Sclerosis is a composite endpoint. It is determined in a 2-step process. The first step assesses whether the patient has had a significant decline in renal or cardiopulmonary involvement. If none of these apply, the second step assesses the probability of improvement by measuring changes in five outcomes and integrating them into a single number using an equation described in Khanna D, Berrocal VJ, et al. [The American College of Rheumatology Provisional Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis. Arthritis and Rheumatology. 2016; 68(2):299-311.]. It incorporates changes in the modified Rodnan skin score, percent predicted forced vital capacity (FVC), patient and physician global assessments, and SHAQ-DI over 1 year. The score ranges from 0 to 1; a higher score indicates better outcome.	Week 52
Secondary	Change From Baseline to Month 12 in PROMIS - Fatigue	The Patient-Reported Outcomes Measurement Information System (PROMIS) 8-question short-form health-reported quality of life measure fatigue domain was administered. The transformed score (T-score) was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., worse outcome).	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in PROMIS - Sleep Disturbance	The Patient-Reported Outcomes Measurement Information System (PROMIS) 4-question short-form health-reported quality of life measure sleep disturbance domain was administered. The transformed score (T-score) was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., better outcome).	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in PROMIS - Sleep Impairment	The Patient-Reported Outcomes Measurement Information System (PROMIS) 8-question short-form health-reported quality of life measure sleep impairment domain was administered. The transformed score (T-score) was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., worse outcome).	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in HAQ-DI - Dressing and Grooming	The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome.	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in HAQ-DI - Hygiene	The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome.	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in HAQ-DI - Arising	The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome.	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in HAQ-DI - Reach	The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome.	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in HAQ-DI - Eating	The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome.	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in HAQ-DI - Grip	The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome.	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in HAQ-DI - Walking	The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome.	Baseline and Week 52
Secondary	Change From Baseline to Month 12 in HAQ-DI - Common Daily Activities	The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome.	Baseline and Week 52

External Links

•   Study Website
•   To learn more about the Scleroderma program at the University of Michigan